(a) Field of the Invention
The invention relates to (S)-(+)-2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]ethanol [hereafter (S)-(+)-hydroxychloroquine] which is useful in the treatment of acute attacks and suppression of malaria due to Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and susceptible strains of Plasmodium falciparum, systemic and discoid lupus erythematosus, and rheumatoid arthritis.
(b) Information Disclosure Statement
Racemic hydroxychloroquine, which is 2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]ethanol (Surrey U.S. Pat. No. 2,546,658, Mar. 27, 1951), and which is sold as the sulfate salt by Sanofi Winthrop Pharmaceuticals under the tradename Plaquenil.RTM. Sulfate, is primarily useful as an antimalarial agent and is also used in treating lupus erythematosus and rheumatoid arthritis.
A. J. McLachlan et al., J. Chromatogr., 570 (No. 1), 119-127, dated Sep. 18, 1991, disclose the high-performance liquid chromatographic separation of the enantiomers of hydroxychloroquine and its major metabolites in biological fluids. The authors acknowledge a gift of S(+)-hydroxychloroquine from Sterling Pharmaceuticals.
J. Iredale et al., J. Chromatogr., 573 (No. 2), 253-258, dated Jan. 17, 1992, disclose the development of a sequential achiral-chiral high-performance liquid chromatographic system for the determination of the enantiomers of hydroxychloroquine and its three major metabolites.
S. E. Tett et al., Br. J. Clin. Pharmac., 26, 303-313 (1988), disclose a dose-ranging study of the pharmacokinetics of racemic hydroxychloroquine following intravenous administration to healthy volunteers. The authors state that the pharmacokinetics of hydroxychloroquine are similar to those of chloroquine.
Chem. Abstr. 92, 69587p (1980) discloses that when administered orally daily for four days beginning at two hours after Plasmodium berger infestation in mice, doses of 5 and 20 mg/kg of the d-enantiomer of chloroquine diphosphate were more effective than corresponding doses of the 1-enantiomer in antimalarial parameters measured, including percentage of cured mice at &gt;7.5 mg/kg; and that the d-enantiomer was also more active than the racemate, but only at subcurative doses.
Chem. Abstr. 90, 132863b (1979) discloses the results of a study of the activity of chloroquine enantiomers against rodent malaria in which it was found that (+)-chloroquine diphosphate was a more active antiplasmodial agent than (-)-chloroquine diphosphate in Plasmodium vinckei-infected mice, and that the activity of (.+-.)-chloroquine diphosphate was between that the two enantiomers.
J. C. Craig et al., J. Org. Chem., 53, 1167-1170 (1988), disclose the absolute configuration of the enantiomers of chloroquine and the synthesis of (R)-(-)-chloroquine by condensation of (R)-(-)-4-amino-1-(diethylamino)pentane of &gt;90% purity with 4,7-dichloroquinoline.
G. Blaschke et al., Chem. Ber., 111, 2732-2734 (1978) disclose the chromatographic separation of the enantiomers of chloroquine as well as their preparation by condensation of (+) and (-)-4-amino-1-(diethyamino)pentane with 4,7-dichloroquinoline.
H. N. Bernstein, Annals of Ophthalmology, 23, 292-296 (1991), presents an analysis of all published cases and Food and Drug Administration reports of retinopathy induced by hydroxychloroquine. The author states that antimalarial therapy, because of a relative lack of systemic side effects compared with other immunomodulating drugs, has been used increasingly over the past 15 years for the treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus, and other predominantly autoimmune disease, and that in the United States, hydroxychloroquine is preferred to chloroquine because it is considered significantly less retinotoxic at the current recommended maximum dose (400 mg/day, according to the FDA and the manufacturer). The author nevertheless notes that physicians are concerned about using drugs with retinotoxic potential at higher dose levels. He then suggests, inter alia, that the risk of true retinopathy is nullified when the maintenance daily dose is based on .ltoreq.6.5 mg/kg body weight and states that even in the absence of a real toxicity risk, it is recommended that a periodic ocular examination program be followed because of the retinotoxic history associated with hydroxychloroquine.